In the years since my laboratory at the NIDA IRP identified the sigma-1 receptor (Sig-1R) in 1982, many preclinical studies have shown that Sig-1Rs and associated ligands are involved in stroke, amnesia, depression, cancer, Alzheimers disease, pain, and psychostimulant addiction. We found here that Sig-1Rs reside at an intracellular organelle called the endoplasmic reticulum (ER) that is responsible for the synthesis of most of proteins in the cell. More specifically, Sig-1Rs localize at a particular subdomain at the ER membrane that directly faces and contacts another intracellular organelle called mitochondrion which produces energy for the cell. Sig-1Rs thus play a very important role in the cell by directly communicating the well-being of the protein synthesis machinery to the energy-producing organalle in the cell. For example, Sig-1Rs regulate calcium transfer and lipid metabolism between the ER and mitochondrion and are thus involved in many cellular processes critical for the proper functioning of the living system. Inasmuch as Sig-1Rs are molecular chaperones that regulate the functionality of proteins by maintaining them at a proper three-domensional configuration, we are examining what proteins, in addition to the IP3 receptors that we have so far discovered, might be chaperoned by Sig-1Rs. In doing so, we might have a better understanding of how this molecular chaperone, the Sig-1R, may play a role in so many diseases. In this fiscal year we found that (1) the Sig-1R can translocate to the plasma membrane to interact with potassium channel Kv1.2 to attenuate the intrinsic excitability of neurons that in turn enhances animal's behavioral responses to cocaine; (2) the Sig-1R chaperones the ER stress sensor IRE1 at the ER-mitochondrion interface and enhances the mitochondrion-ER-nucleus signaling for cellular survival; and (3) the ER-mitochondrion interface can also provide proper Ca2+ signaling from ER into mitochondria by utilizing the antiapoptotic protein BclxL to activate IP3 receptors at the interface.